A gyűjtőcsatorna meghatározó szerepe a vese lokális renin-angiotenzin rendszerében

A renin-angiotenzin rendszer szervezetünk egyik legjelentősebb hormonális rendszere, amelynek juxtaglomerularis apparátusban történő szabályozása és szerepe jól ismert. Jelen összefoglaló a vese embrionális fejlődésével párhuzamot állítva a gyűjtőcsatorna renintermelését írja le, valamint ennek lokális szerepét és terápiás célpontként szolgáló lehetőségeit igyekszik feltárni. Nemrégiben került leírásra, hogy krónikus angiotenzin- II-kezelés során, két vese-, egy klip modellben, illetve diabetes mellitusban a gyűjtőcsatorna jelenti az intrarenalis (pro)renintermelés legfőbb helyét. Ebben a lokalizációban a (pro)renin előtt út nyílhat az interstitialis renin-angoitenzin rendszer komponensek, a szisztémás keringés és a nemrégiben leírásra került (pro)reninreceptor felé. A (pro)renin saját receptorán keresztül intracelluláris profibroticus utakat képes aktiválni, így egyúttal potenciálisan új célpontja lehet a hypertoniához kapcsolódó vagy diabeteses nephropathia kezelésének, illetve eszköze a krónikus vesekárosodást előidéző folyamatok korai diagnosztizálásának. Orv. Hetil., 2013, 154, 643–649

A szteroid-rezisztens nephrosis szindróma genetikai vizsgálata Magyarországon

Bevezetés: A szteroid-rezisztens nephrosis szindróma egy rossz prognózisú kórkép. Immunológiai és monogénes formájának elkülönítése fontos, mert kezelésük különböző, de rendszerint csak genetikai vizsgálattal lehetséges. Célkitűzés, beteganyag: Célunk a gyakran kóroki NPHS2, WT1 és NPHS1 gének vizsgálatának hazai bevezetése volt. Ötvennyolc SRNS vagy nefrotikus mértékű proteinuria miatt gondozott gyermeket és fiatal felnőttet vizsgáltunk. Eredmények: Tizenegy/49 családban találtunk NPHS2, 5/19 családban WT1 és 1/5 gyermeknél NPHS1 mutációt. A tünetek megjelenésének idejében, a vesefunkció romlásának ütemében és a társuló extrarenális érintettségben jelentős különbség volt a különböző gének, és azok különböző mutációi között is. Míg újszülött- és csecsemőkori megjelenés esetén az esetek felében, a gyermekkori esetek mindössze negyedében találtunk kóroki mutációt. Következtetés: Szteroid-rezisztens nephrosis szindrómában a mutáció ismerete lehetővé teszi a genetikai tanácsadást, a prognózis megítélését és meghatározza a terápiát

Calcineurin-Inhibition Results in Upregulation of Local Renin and Subsequent Vascular Endothelial Growth Factor Production in Renal Collecting Ducts.

BACKGROUND: Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD). METHODS: Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining. RESULTS: The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands. CONCLUSIONS: Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity

Visualization of Calcium Dynamics in Kidney Proximal Tubules

Intrarenal changes in cytoplasmic calcium levels have a key role in determining pathologic and pharmacologic responses in major kidney diseases. However, cell-specific delivery of calcium-sensitive probes in vivo remains problematic. We generated a transgenic rat stably expressing the green fluorescent protein-calmodulin-based genetically encoded calcium indicator (GCaMP2) predominantly in the kidney proximal tubules. The transposon-based method used allowed the generation of homozygous transgenic rats containing one copy of the transgene per allele with a defined insertion pattern, without genetic or phenotypic alterations. We applied in vitro confocal and in vivo two-photon microscopy to examine basal calcium levels and ligand- and drug-induced alterations in these levels in proximal tubular epithelial cells. Notably, renal ischemia induced a transient increase in cellular calcium, and reperfusion resulted in a secondary calcium load, which was significantly decreased by systemic administration of specific blockers of the angiotensin receptor and the Na-Ca exchanger. The parallel examination of in vivo cellular calcium dynamics and renal circulation by fluorescent probes opens new possibilities for physiologic and pharmacologic investigations

NPHS2 homozygous p.R229Q variant: potential modifier instead of causal effect in focal segmental glomerulosclerosis

BACKGROUND: The pathogenicity of the NPHS2 homozygous p.R229Q variant in steroid-resistant nephrotic syndrome (SRNS) is doubtful. While it has been reported in unaffected controls, it is enriched in patients with SRNS, suggesting pathogenicity. CASE-DIAGNOSIS/TREATMENT: A family with three members homozygous for the NPHS2 p.R229Q variant is presented: a 37-year-old patient who was diagnosed with proteinuria at age 7 months, focal segmental glomerulosclerosis (FSGS) at age 20 years, and end-stage renal disease (ESRD) at age 33 years, his 59 year-old father and his 40 year-old brother, both unaffected with no proteinuria. The affected son also harbors a heterozygous de novo, truncating PAX2 mutation (c.76dupG, p.V26Gfs*28), which can explain his chronic renal failure but which is rarely associated with FSGS. CONCLUSIONS: This family provides further evidence that homozygous p.R229Q in itself may not cause FSGS. Nevertheless, the rare association of FSGS to a PAX2 mutation may reflect the modifier effect of p.R229Q in the homozygous state. Such a modifier effect can also explain its enrichment in SRNS patients. Patients with homozygous p.R229Q should be screened for the causative mutation in a second gene

NPHS2 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome.

BACKGROUND: The most frequently mutated gene of steroid- resistant nephrotic syndrome (SRNS) is NPHS2. Current guidelines propose the sequencing of all NPHS2 exons only in childhood- onset SRNS. METHODS: A cohort of 38 Hungarian patients with childhood-onset nephrotic-range proteinuria was screened for NPHS2 mutations. The frequency of the p.V290M mutation in late- onset SRNS was examined in the French and PodoNet cohorts. RESULTS: Of the 38 Hungarian patients screened, seven carried NPHS2 mutations on both alleles, of whom two-diagnosed with proteinuria through school screening programs at the age of 9.7 and 14 years, respectively-did not develop nephrotic syndrome in childhood. The first, an 18-year-old boy, homozygous for p.V290M, has never developed edema. The second, a 31-year-old woman-compound heterozygous for p.V290M and p.R138Q-was first detected with hypoalbuminemia (<30 g/l) and edema at the age of 24.3 and 27.5 years, respectively. Both patients currently have a normal glomerular filtration rate. The mutation p.V290M was carried by three of the 38 patients in the Hungarian cohort, by two of the 95 patients with late-onset SRNS in the PodoNet cohort and by none of the 83 patients in the French cohort. CONCLUSIONS: We propose that not only the p.R229Q variant, but also the p.V290M mutation should be screened in Central and Eastern European patients with late-onset SRNS